EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1985327152  42 EDIKKIFHILDKDRSGFIEEDELKFILKGFTpNGRDLSDKETKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE-EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

calmodulin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1985327152  40 SQEDIKKIFHILDKDRSGFIEEDELKFILkgfTPNGRDLSDKETKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:PTZ00184   82 SEEEIKEAFKVFDRDGNGFISAAELRHVM---TNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1985327152   40 SQEDIKK---IFHILDKDRSGFIEEDELKFILkgftpngrdLSDKETKTLLVA----GDKDGDGKIGIDEFI 104
Cdd:smart00027   5 SPEDKAKyeqIFRSLDKNQDGTVTGAQAKPIL---------LKSGLPQTLLAKiwnlADIDNDGELDKDEFA 67

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152   9 AEEIKAAVAAFSAAESFSHKKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEEDELKFILKGFTPNGRDLSDKETKTLLV 88
Cdd:cd16251     1 AKDIEKAPSAFRAHGSFNYKKFFEHVGLKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFSIAGRDLTDEETKALLA 80

                          90       100
                  ....*....|....*....|.
gi 1985327152  89 AGDKDGDGKIGIDEFITLVAE 109
Cdd:cd16251    81 AGDTDGDGKIGVEEFATLVAG 101

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  23 ESFSHKKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEEDELKFILKGFTPNGRDLSDKETKTLLVAGDKDGDGKIGIDE 102
Cdd:cd16255    15 DSFNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTDAETKAFLKAGDSDGDGKIGVEE 94

                  ....*
gi 1985327152 103 FITLV 107
Cdd:cd16255    95 FQALV 99

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1985327152  43 DIKKIFHILDKDRSGFIEEDELKFILKGFtpnGRDLSDKETKTLLVAGDKDGDGKIGIDEFITLVA 108
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSL---GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1985327152  42 EDIKKIFHILDKDRSGFIEEDELKFILKGFtpngrDLSDKETKTLLVAGDKDGDGKIGIDEFITLVAE 109
Cdd:COG5126    69 PFARAAFDLLDTDGDGKISADEFRRLLTAL-----GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1985327152  37 KKKSQEDIKKIFHILDKDRSGFIEEDELKFILKGF-----TPNGRDLSDKETKTLLVAGDKDGDGKIGIDEFITL 106
Cdd:cd15902    85 PLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKL 159

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  45 KKIFHILDKDRSGFIEEDELKfilKGFTPNGRDLSDKETKTLLVAGDKDGDGKIGIDEFI 104
Cdd:cd16184    70 KQVFQQFDRDRSGSIDENELH---QALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFI 126

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  37 KKKSQEDIKKIFHILDKDRSGFIEEDELKFILK------GFTPNGRDLSDketktLLVAGDKDGDGKIGIDEFITLVAEA 110
Cdd:NF041410   58 DDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPppppppDQAPSTELADD-----LLSALDTDGDGSISSDELSAGLTSA 132

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  28 KKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEEDELKFILKGFtpnGRDLSDKETKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:PTZ00183    3 KRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSL---GFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIM 79

                  .
gi 1985327152 108 A 108
Cdd:PTZ00183   80 T 80

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1985327152  44 IKKIFHILDKDRSGFIEEDELKFILKGFTPNgrdLSDKETKTLLVAGDKDGDGKIGIDEFITL 106
Cdd:cd15898     2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIR---VSEKELKKLFKEVDTNGDGTLTFDEFEEL 61

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1985327152  40 SQEDIKKIFHILDKDRSGFIEEDELKFILKGFTPNGRDLSDKE-------TKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:cd16179    93 SSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNDVSedklieyTDTILQLFDRNKDGKLQLSEMARLL 167

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  45 KKIFHILDKDRSGFIEEDELKFILKGFtpnGRDLSDKETKTLLVAGDKDGDGKIGIDEFI 104
Cdd:cd16180    70 RRLFRRFDRDRSGSIDFNELQNALSSF---GYRLSPQFVQLLVRKFDRRRRGSISFDDFV 126

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1985327152  35 GLKKKSQEDIKKIFHILDKDRSGFIEEDELKFILKGFTPNGR---DLSDKE--TKTLLVAGDKDGDGKIGIDE 102
Cdd:cd16179   181 GAGKLTREDIDRVFALYDRDNNGTIENEELTGFLKDLLELVQedyDEQDLEefKEIILRGWDFNNDGKISRKE 253

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1985327152  39 KSQEDIKKIFHILDKDRSGFIEEDELKFILKGFTPNGRDLSDKE-----TKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:cd16176    82 KSSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANKPFDESkleeyTHTMLKMFDSNNDGKLGLTEMARLL 155

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1985327152  47 IFHILDKDRSGFIEEDELKFIL-----KGFTPngrdlsdkETKTLLVAG-DKDGDGKIGIDEFITL 106
Cdd:cd16183     5 VFQRVDKDRSGQISATELQQALsngtwTPFNP--------ETVRLMIGMfDRDNSGTINFQEFAAL 62

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1985327152  30 FFEMVGLK---KKSQEDIKKIFHILDKDRSGFIEEDELKFILKGFtpnGRDLSDKETKTLLVAGDKDGDGKIGIDEFITL 106
Cdd:PTZ00183   75 FLDIMTKKlgeRDPREEILKAFRLFDDDKTGKISLKNLKRVAKEL---GETITDEELQEMIDEADRNGDGEISEEEFYRI 151

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t specific neurons of the central and peripheral nervous system. It possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1985327152  52 DKDRSGFIEEDELK-FILKGFTPNGRDLSDKE----TKTLLVAGDKDGDGKIGIDEFITLV 107
Cdd:cd16177   100 DTDRSGYIEANELKgFLSDLLKKANRPYDEKKlqeyTQTILRMFDLNGDGKLGLSEMARLL 160

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1985327152  48 FHILDKDRSGFIEEDElkfILKGFTPNGRDLSDKETKTLLVAGDKDGDGKIGIDEFITLVA 108
Cdd:cd16185    72 FEQRDTSRSGRLDANE---VHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIELCI 129

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1985327152  45 KKIFHILDKDRSGFIEEDELKFILK--GFTPNGRdlsdkeTKTLLVAGDKDGDGKIGIDEFI 104
Cdd:cd16196    74 KRVFKLFDTDGSGSFSSFELRNALNsaGFRLSNA------TLNALVLRYSNKDGRISFDDFI 129